Sudden cardiac death (SCD) is defined as the unexpected death due to cardiac causes of persons with or without underlying cardiac disease, with no other known cause for death. SCD occurs within a short period of time, for example, generally within one hour, following the onset of symptoms (if any symptoms are encountered).
SCD is a major public health problem as it has reached epidemic proportions, responsible for at least 325,000 deaths per year in the United States alone. (See Goldberger. Circulation. 2008; 118:000-000; Zipes, D. P., et al., ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death—Executive Summary. Circulation, 2006: p. CIRCULATION AHA.106.178104.). SCD is the second leading cause of death in the U.S., responsible for slightly less deaths than myocardial infarction. Despite the decreased incidence of all cardiac deaths secondary to improved medical treatment, SCD continues to represent about half of all cardiac deaths. (See Ezekowitz. Ann Intern Med. August 2007; 21; 147(4):251-62).
Most cases of SCD are related to cardiac ventricular arrhythmias (ventricular tachycardia, or VT). Coronary artery disease is associated with the largest number of SCDs. Acute coronary syndrome (ACS) can lead to malignant arrhythmias that are the result of ischemia. Additionally, coronary artery disease (CAD) may lead to microscopic or macroscopic scar formation that can represent substrate for malignant arrhythmias.
Congestive Heart Failure (CHF) with or without CAD is another cardiac illness associated with a significant risk for SCD. In addition, cardiomyopathy, left ventricular hypertrophy (LVH), myocarditis, hypertrophic cardiomyopathy, congenital coronary artery anomalies, and myxomatous mitral valve disease are associated with an increased SCD risk. Finally, the presence of channelopathies such as Brugada syndrome and congenital heart disease or acquired long QT syndrome, idiopathic ventricular fibrillation (VF), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), catecholaminergic VT, and Wolff-Parkinson-White (WPW) syndrome increase the risk of SCD.
Implantable cardioverter-defibrillator (ICD) therapy has significantly decreased the occurrence of SCD in high-risk patients, but has done little to reduce the overall incidence of SCD nationally. (See Bardy. N Engl J Med. 2005 Jan. 20; 352(3):225-37). This is explained by the fact that two-thirds of patients suffering SCD are in low or intermediate risk groups, resulting in the greatest absolute number of patient deaths. However, multiple trials have repeatedly demonstrated that patients in low and intermediate risk groups do not benefit from prophylactic ICD placement. This result demonstrates the lack of sensitivity and specificity of contemporary methods used to stratify individuals for SCD risk. The ability to prevent SCD using ICDs is of great importance, and it demonstrates the critical need for a highly sensitive and highly specific method for identifying individuals at risk for SCD.
Based on the foregoing, the identification of individuals presently considered to have no, low, or intermediate risk for SCD as defined by presently available risk-stratification methods—but in reality are at high risk—continues to be a major public health concern.
Presently available techniques for the identification of individuals at risk for SCD include medical history, (e.g., history of coronary artery disease (CAD), congestive heart failure (CHF), decreased left ventricular ejection fraction (LVEF), prior myocardial infarction, structural or ischemic heart disease), Holter monitoring, heart rate variability analysis, signal averaged electrocardiography (SAECG), microvolt T-wave alternans analysis, ambulatory ECG monitoring, metabolic factors and/or parasympathetic tone, heart rate turbulence studies, baroreceptor sensitivity studies and the presence of myocardial scar as detected using magnetic resonance imaging (MRI). Severely reduced LVEF and the presence of advanced CHF (NYHA Class III or IV) currently serve as the main identifiers for patients at high-risk for SCD and, therefore, for identifying who may benefit from ICD therapy. (See Epstein. Heart Rhythm. 2008 June; 5(6):934-55; Chugh. Nat Rev Cardiol. 2010 Jun. 7 (6): 318-326, available at http://www.ncbi.nlm.nih. gov/pmc/articles/PMC3052394/). However, no presently available method, including those listed above, alone or in combination, has clinically acceptable sensitivity or specificity for the identification of individuals at risk for SCD. A detailed discussion of some exemplary techniques is provided herewith.